Project 2: Multi-Ethnic Analysis for Alzheimer Disease

项目 2：阿尔茨海默病的多种族分析

基本信息

批准号：
10654541
负责人：
Giuseppe Tosto
金额：
$ 67.48万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654541
关键词：
Affect African African American African American population African ancestry Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Awareness Biology Cuban Detection Disease Dissection Ethnic Origin Ethnic Population Etiology European European ancestry Event Exhibits Genes Genetic Genetic Risk Genetic Variation Genetic study Genomic Segment Genomics High Prevalence Hispanic Incidence Individual Inherited Latinx Linkage Disequilibrium Maps Meta-Analysis Modeling Native American Ancestry Native Americans Not Hispanic or Latino Output Pattern Population Population Heterogeneity Prevalence Puerto Rican Recording of previous events Research Resources Risk Role Shapes Testing Variant Work admixture mapping causal variant cohort genetic architecture genetic risk factor genome-wide genomic data genomic locus multi-ethnic novel phenotypic data protective allele rare variant recruit risk variant variant detection

Affect African African American African American population African ancestry Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Awareness Biology Cuban Detection Disease Dissection Ethnic Origin Ethnic Population Etiology European European ancestry Event Exhibits Genes Genetic Genetic Risk Genetic Variation Genetic study Genomic Segment Genomics High Prevalence Hispanic Incidence Individual Inherited Latinx Linkage Disequilibrium Maps Meta-Analysis Modeling Native American Ancestry Native Americans Not Hispanic or Latino Output Pattern Population Population Heterogeneity Prevalence Puerto Rican Recording of previous events Research Resources Risk Role Shapes Testing Variant Work admixture mapping causal variant cohort genetic architecture genetic risk factor genome-wide genomic data genomic locus multi-ethnic novel phenotypic data protective allele rare variant recruit risk variant variant detection

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项目摘要

PROJECT SUMMARY/ABSTRACT: PROJECT 2 (Multi-Ethnic Analysis for Alzheimer Disease) Alzheimer's disease (AD)’s etiology is still relatively unexplained but substantial evidence supports a strong genetic component. Most AD genetic studies have focused on European (EU) descent individuals, despite Hispanic/Latinx (HL, genetically admixed of EU, African (AF) and Native American (NA) ancestry) and African Americans (AA, genetically admixed of EU and AF ancestry) having higher prevalence and incidence of AD. Thus, it is important to understand how ancestry affects AD risk among diverse populations to provide better models of risk. Overall, we hypothesize that diverse populations harbor novel AD risk/protective alleles that are rare or absent in other populations or that they have modifiers that alter the effects of common risk alleles, and specifically that AF and NA ancestries enhances AD risk. ʺRecruitment and Retention for Alzheimer’s Disease Diversity Genetic Cohorts in the ADSP (READD-ADSP) will add new, diverse cohorts that augment the existing pool of genomic data. To test our hypothesis, we will perform admixture mapping in AA and HL, assuming causal variants/genes are more frequently on chromosomal segments inherited from the ancestral population with higher AD prevalence. We will also investigate universal genetic loci (i.e. those that confer risk in most or all populations) by performing a large trans-ethnic study that includes AA, HL, as well as EU and AF ancestral populations. This approach will boost statistical power, detection of rare variant and dissection of AD genetic architecture within populations. We will also test whether associating and/or modifying loci differ from the genomic background in terms of past selective events that may have shifted AD risk. To study the diversity of AD genetic risk, we will: 1) Determine the AF and NA origins of genetic variation in AD, using admixed populations and investigate ethnic-specific modifiers. We will estimate global and local ancestry in each HL and AA cohort separately, in order to investigate their association with AD and prioritize the genomic segments where higher AF or NA ancestry confers higher AD risk. These segments will be fine-mapped employing resources developed in Project 1 and with ancestry-aware association tests. We will also examine whether the effects of known or newly-identified AD-associated loci are altered by ancestry background. 2) We will perform trans-ethnic meta-analysis across AF, AA, HL, NHW cohorts using single-marker and gene- based outputs from Project 1 but also we will meta-analyze local ancestries that are shared across admixed cohorts (e.g. AF component across AA, Puerto Ricans, Cubans etc.). Finally, 3) we will perform explicit tests of selection on AD-associated loci and their modifying loci prioritized by Project 1 and 2 and determine whether patterns of evolutionary history are consistent across diverse populations with patterns of association.

项目摘要/摘要：项目2（阿尔茨海默氏病的多种族分析）阿尔茨海默氏病（AD）的病因仍然相对无法解释，但大量证据支持了强大的证据遗传成分。大多数AD遗传研究都集中在欧洲（EU）血统，绝望西班牙裔/拉丁裔（HL，通常由欧盟，非洲（AF）和美国原住民（NA）血统）和非洲人美国人（AA，通常以欧盟和AF祖先的混合）具有更高的AD患病率和发病率。这一点，重要的是要了解祖先如何影响潜水员人群中的广告风险以提供更好的风险模型。总体而言，我们假设潜水员人口具有新颖的广告风险/保护等位基因在其他人群中很少见或不存在，或者它们具有改变共同作用的修饰符风险等位基因，特别是AF和NA祖先会增强AD风险。 ʺ培训和保留 ADSP中的阿尔茨海默氏病多样性遗传人群（ReadD-ADSP）将增加新的，潜水员的同龄人群增加现有的基因组数据库。为了检验我们的假设，我们将在AA中执行混合映射和HL，假设因果变体/基因更频繁地在继承的染色体段上 AD患病率较高的祖先人群。我们还将研究普遍的遗传环境（即大多数或所有人群的会议风险）通过进行大型跨种族研究，包括AA，HL以及欧盟和AF祖先人口。这种方法将促进统计能力，检测稀有变体和在人群中解剖AD遗传结构。我们还将测试是否关联和/或修改在过去的选择性事件方面，基因素与基因组背景不同，这些事件可能改变了AD风险。学习 AD遗传风险的多样性，我们将：1）确定AD中遗传变异的AF和NA起源，使用混合种群并研究了种族特异性的修饰符。我们将估计全球和地方血统为了研究其与AD的关联并优先考虑基因组，在每个HL和AA队列中分别进行较高的AF或NA祖先承认较高的AD风险的细分市场。这些细分市场将被细化采用项目1中开发的资源以及祖先感知的协会测试。我们还将检查无论是已知的还是新识别的广告相关局部的影响，都会因祖先背景而改变。 2）我们将使用单标记和基因进行AF，AA，HL，NHW队列进行跨种族的荟萃分析项目1的基于基于的产出，但我们也将元分析当地祖先，这些本地祖先共享在混合式的情况下队列（例如，遍布AA，波多黎各人，古巴人等的AF组成部分）。最后，3）我们将执行明确的测试项目1和2优先考虑与广告相关基因座的选择及其修改的基因座，并确定是否在具有关联模式的潜水员人群中，进化史的模式是一致的。